Sharp increases in substance use rates among youth in Mexico are a major concern, both in Mexico and the US. Although the Mexican government has elevated substance abuse prevention as a national priority, there are few school-based universal prevention programs to choose from that are culturally grounded, empirically tested, and shown to be efficacious. This study aims to address this gap by adapting, implementing, and testing the keepin' it REAL (kiR) prevention intervention in Mexico's three largest cities: Mexico City, Guadalajara, and Monterrey. kiR is a model program for middle school students on the US National Registry of Effective Programs and Practices, shown to be efficacious and cost-effective in reducing substance use among large multi-ethnic and Mexican American samples in the US. The proposed study will leverage the bi-national research team's expertise in developing and adapting kiR and build upon a series of feasibility studies across Mexico which showed that kiR's core elements are applicable there. However, evidence also suggested that further adaptation is needed to enhance the intervention's cultural fit. During the proposed study's Phase 1, students and teacher-implementers in three schools-one from each of the cities-will provide feedback about the original curriculum and identify culturally and contextually relevant scenarios and examples. The bi-national research team-including original kiR curriculum designers-will collaborate to ensure cultural applicability in Mexico and fidelity to core elements of kiR. In Phase 2, the efficacy of the culturally adapted Mexican version of kiR, relative to the original version of kiR and to a control condition, will be tested through an inten-to-treat analysis in a randomized controlled trial with 4,050 7th grade students in 27 middle schools, 9 from each city. The study will investigate and incorporate into the curriculum gender specific experiences with drug offers and appropriate drug resistance strategies in the Mexican context that may impact the youths' risk of substance use and their responsiveness to prevention programs. In light of rising violence in Mexico, a secondary aim of the study is to investigate how youths' perpetration, victimization, and witnessing of violence may moderate the efficacy of kiR in Mexico. The study will create knowledge relevant to efficacious prevention approaches for Mexican-heritage youth on both sides of the US-Mexico border. Prevention science will be advanced by understanding how culturally influenced gender role norms affect substance use offers, attitudes, and behaviors, as well as the success of universal prevention programs. In addition, the study will add to knowledge on how to execute collaborative, cross-national, translational prevention intervention research.